Disseminated neuroblastoma, a common form of childhood cancer, has been treated with a variety of chemotherapeutic drugs. Drug induced remissions are frequently noted, but the tumor generally returns, resistant to the drugs used. As the drug resistance mechanisms were unknown for this tumor, we used the genetically homogenous C46 clone of the spontaneous murine neuroblastoma C-1300 in monolayer cell culture, to isolate and biochemically characterize variants resistant to a series of antifolates, nucleoside analogues, anthracyclines and microtubule disrupters. Resistance mechanisms, involving alterations in drug uptake and retention, or the activities of affected enzymes, proved to be neuroblastoma specific. In demonstrating the parallel resistance of these clones in their syngeneic host, the Ajax mouse, alterations in tumorigenicity were noted suggesting changes in cell surface glycoproteins. This and collateral sensitivity to several inhibitors of glycosylation led us to examine the resistant cell's surface glycoproteins and glycolipids using whole cell surface radiolabeling techniques and fractionation by 2-dimensional gel electrophoresis and lectin-chromatography. One maytansine resistant mutant, as is typical of membrane mediated resistant cells, was cross resistant to a wide range of lipophilic drugs, and unable to take up colchicine despite a normal content of cytoplasmic tubulin, proved to be 98% deficient in a cell surface glycoprotein, MW equals 90,000 daltons, pI equals 5.95. We propose the examination of other drug selected mutants, cross-resistant to maytansine, and a drug sensitive revertant, for glycoprotein alterations, to establish causality, and to determine whether this and similarly altered glycoproteins on our other mutants represent a transcriptional, translational, post-translational or membrane assembled effect. Mindful of species variation seen in other drug resistance mechanisms, we propose to contrast this mechanisms with that of diploid human neuroblastoma SK-SY-5Y maytansine resistant clones and to study the effect of the membrane glycosylation inhibitor, tunicamycin, on this drug resistance and altered tumorigenesis in an effort to understand and improve the chemotherapy of this tumor.